Although cytotoxic CD8+ T cells (CTL) play an important protective role during HIV infection, a number of studies have revealed that these important cells may suffer from functional defects that impair their efficiency in controlling HIV virus. Studies from our laboratory have revealed that HIV-specific CD8+ T cells exhibit increased susceptibility to apoptosis. We have shown that HIV-specific CD8+ T cells are very sensitive to CD95/Fas-induced apoptosis and that HIV-infected macrophages can kill HIV-specific CD8+ T cells by a CD95/Fas-dependent mechanism. In addition, HIV-specific CD8+ T cells lack terminal differentiation and CD95/Fas apoptosis may be involved in this skewing of differentiation. The ability of HIV-specific CD8+ T cells therefore to kill infected cells and their differentiation may be compromised due to CD95/Fas-mediated apoptosis of these cells. Recently, we have found a decrease in the anti-apoptotic molecules Bcl-2 and Bcl-XL in HIV-specific CD8+ T cells, suggesting that this may account at least partially for the increased apoptosis sensitivity. Based on our findings from in vitro studies of HIV-specific CD8+ T cells we hypothesize that HIV-specific CD8+ T cells are in a proapoptotic state due to an imbalance of pro- and anti-apoptotic factors and that this is the result of priming in the absence of HIV-specific CD4+ T cell help, chronic stimulation or a combination of both. This chronic stimulation, aberrant priming or both, results in increased apoptotic potential and defective proliferative capacity. In the current proposal we will investigate the molecular mechanism(s) involved in the increased apoptosis sensitivity of HIV-specific CD8+ T cells. We will also determine the in vivo mechanisms in mice that result in virus-specific CD8+ T cells that exhibit increased apoptosis sensitivity, functional defects and molecular profiles similar to HIV-specific CD8+ T cells. Understanding the mechanism behind these defects of HIV-specific CD8+ T cells may allow for the restoration of survival or function of HIV-specific CD8+ T cells which in turn would have a profound effect in controlling or clearing HIV. Finally, such an understanding will be critical for the development of vaccines that provide long lasting CTL immunity.